Obesity and its associated disorders are common and very serious public health problems in the United States and throughout the world. Upper body obesity is the strongest risk factor known for type 2 diabetes mellitus and is a strong risk factor for cardiovascular disease. Obesity is a recognized risk factor for hypertension, atherosclerosis, congestive heart failure, stroke, gallbladder disease, osteoarthritis, sleep apnea, reproductive disorders such as polycystic ovarian syndrome, cancers of the breast, prostate, and colon, and increased incidence of complications of general anesthesia.
Obesity reduces life-span and carries a serious risk of the co-morbidities listed above, as well disorders such as infections, varicose veins, acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease (Rissanen et al., Br. Med. J. 301:835-837 (1990)). Obesity is also a risk factor for the group of conditions called insulin resistance syndrome, or “Syndrome X” and metabolic syndrome. The worldwide medical cost of obesity and associated disorders is enormous.
Obesity remains a poorly treatable, chronic, essentially intractable metabolic disorder. Accordingly, a need exists for new therapies useful in weight reduction and/or weight maintenance in a subject. Such therapies would lead to a profound beneficial effect on the subject's health.
The present invention provides methods and compositions useful in the control, treatment, and prevention of obesity and obesity-related conditions, disorders, and diseases, such as those referenced above.
Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic peptide (PP) are members of the PP family characterized by a 36-amino acid sequence with a tyrosine amide at the carboxy-terminus and six conserved C-terminal amino acids.
NPY is a wide spread neuropeptide with multiple actions in various parts of both central and peripheral nervous systems, acting through a number of different receptor subtypes in man such as Y1, Y2, Y4 and Y5. There are four well-established types of PP-fold peptide receptors in man, Y1, Y2, Y4 and Y5, which all recognize NPY1-36 and PYY1-36 with similar affinity. Affinity studies suggest that the Y4 receptors bind PP with a subnanomolar affinity corresponding to the concentrations found in plasma, whereas NPY and PYY are recognized with much lower affinity.
The NPY receptors are responsible for many diverse physiologic actions including feeding regulation, energy homeostasis, locomotion, seizure, thermoregulation, circadian rhythms, anxiety, cardio-respiratory function, and fertility. PYY(3-36), a major circulating form of PYY corresponding to residues 3-36 of PYY, interacts with at least three NPY receptor subtypes (NPY1, NPY2, and NPY5), and PP interacts with the NPY1, NPY4 and NPY5 receptors. See Balasubramaniam et al., “Neuropeptide Y (NPY) Y4 Receptor Selective Agonists Based on NPY(32-36): Development of an Anorectic Y4 Receptor Selective Agonist with Picomolar Affinity”, J. Med. Chem., 49:2661-2665 (2006).
PP is known to play an important role in the control of food intake and long term energy balance. Sainsbury et al., “Y4 Receptors and Pancreatic Polypeptide Regulate Food Intake via Hypothalamic Orexin and Brain-derived Neurotropic Factor Dependent Pathways”, Neuropeptides, 44:261-268 (2010). PP-fold peptides and analogs of these have been investigated for use in treating obesity and associated diseases, including for example, Prader Willi's syndrome, based on the demonstrated effect of PP levels in animal models and in man. It has been shown since the mid seventies that PP affects food intake in rodents. Evidence from rodent studies has shown that PP is in fact a powerful and efficient anorexigenic peptide when administered peripherally, influencing food intake, energy metabolism, and body weight. See, e.g., Asakawa et al., “Characterization of the Effect of Pancreatic Polypeptide in the Regulation of Energy Balance”, Gastroenterology, 124:1325-1336 (2003).
Additionally, obese humans have shown low basal levels of PP and PYY as well as lower meal responses of these peptides. In 1993, it was reported that infusion of PP in obese patients with Prader Willi's syndrome decreased food intake. In 2003, this finding was confirmed by infusion of PP in normal human subjects where a long lasting suppression of appetite and reduced food intake over 24 hours was observed. See Batterham et al., “Pancreatic Polypeptide Reduces Appetite and Food Intake in Humans”, J. Clin. Endocrinol. Metab., 88:3989-3992 (2003). Further clinical studies have since demonstrated a dose-dependent correlation between PP levels in humans and food intake. See, e.g., Jesudason et al., “Low-dose Pancreatic Polypeptide Inhibits Food Intake in Man”, J. Nutrition, 97:426-429 (2007); and Schmidt et al., “A Role for Pancreatic Polypeptide in the Regulation of Gastric Emptying and Short Term Metabolic Control”, J. Clin. Endocrinol. Metab., 90(9):5241-5246 (2005).
Additionally, it has been shown that PP has no effect on appetite or food intake in Y4 knock out animals. See Lin et al., “Critical Role of Arcuate Y Receptors and the Melanocortin System in Pancreatic Polypeptide-Induced Reduction in Food Intake in Mice”, PloS ONE, 4(12):1-10 (December 2009). This demonstrates that the PP dose-dependent effect on food intake is mediated through the Y4 receptor.
NPY2 agonists and NPY4 agonists have previously been described as useful in preparations, formulations, pharmaceutical compositions, and administration routes, for treatment of obesity and associated diseases, for example, in U.S. Publication No. 2002/0141985 and PCT Publication No. WO 2005/077094.
For treating conditions responsive to Y4 receptor modulation, such as obesity and intestinal hypersecretion, it would be desirable to use PP-fold peptides or peptide mimics such as small molecules which were specific for the Y4 receptor. In particular, it would be highly desirable to use such agents which are selective for the Y4 receptor over the Y1 receptor, as activation of the Y1 receptor is expected to potentially cause unwanted cardiovascular and renal side effects, such as vasoconstriction and natriuresis. Additionally, Y4 receptors are expressed in specific regions of the brain relative to other Y receptors, such that Y-4 specific compounds may have a greater impact in reducing food intake with fewer side effects, such as nausea. See Lin et al., at p. 9.
Thus, use of selective and efficacious Y4 receptor agonists over Y1 and Y2 receptor agonists would be particularly useful in diseases and conditions susceptible to Y4 receptor activation.
The present invention relates to novel substituted adipic acid amides which have the ability to activate, partially activate and/or modulate the NPY4 receptor. Such compounds are therefore potentially useful for the treatment of obesity, to control appetite, feeding, food intake, energy expenditure, caloric intake, gastric motility, diabetes and other related conditions, including those referenced above and elsewhere herein.